Modern parenteral pharmaceuticals have well-defined and well-established manufacturing requirements to meet regulatory and
market needs. First and foremost, injectable drugs must be free of all microorganisms. To achieve that aim, they are packaged
aseptically in a Class 100 cleanroom with strict limits on viable and particulate contamination. (Cleanrooms are classified
by the number of particles larger than 0.5 µm in each ft3 of air.) Production personnel wear gowns, gloves, goggles, and hair and shoe covers to keep the drug from being exposed to
human-borne materials because humans are the single biggest source of contamination in pharmaceutical production. Aseptic
operations are not truly sterile although the products produced are labeled sterile. All products, including those that are
terminally sterilized by steam, still have a probability for a non-sterile unit. In the case of aseptic processing, that probability
is clearly higher.
Typical parenteral doses are filled in vials, cartridges, syringes, and ampoules. Usually, an automated parenteral production
line consists of a washer to clean the glass containers, a depyrogenation tunnel to dry and sterilize all surfaces, and a
filler (with companion check-weigher to ensure accurate dosages). The filled vials are stoppered and covered with an aluminum
cap. The final product is inspected manually, labeled, and inserted in a carton with accompanying patient insert information.
Lyophilized products are filled in liquid form but are then placed in a freeze-dryer, which removes the water and completes
the sealing process.
An alternative to vials is the glass ampoule. Ampoule filling machines seal glass tops with a gas flame or CO2 laser that melts the glass and seals products inside. The advantage is that the drug contacts only one material: glass. Disadvantages
include the possibility of glass reactivity with protein products and the fact that the glass tops are snapped off for use,
creating the possibility of tiny glass fragments entering the formulation.
A filling machine in operation
Recent trends in fill and finish include the development of barrier isolation systems. Such machines reduce the need for a
cleanroom by enclosing the fill operation. This design reduces the risk of introduced human-borne contaminants. Cleanroom
conditions are reproduced in a cost-effective, minimal area that is maintained and serviced in aseptic conditions. Barrier
isolators are rapidly gaining acceptance in the industry and by FDA because they significantly reduce the chance of opportunistic
microorganisms contamination. Barrier systems may be unique to the product and process being used. The major advantage of
an isolator is the ability to sterilize equipment and avoid traditional aseptic filling. The major disadvantages are lack
of flexibility, difficulty in cleaning, and complexity of design — especially for lyophilized products.
Use of BFS machinery allows protein solutions to remain in aqueous form because they are not exposed to the atmosphere. BFS
uses in-line machinery to form a plastic container, fill the container, and then seal it. Critical environmental exposure
is protected by a HEPA-filtered air shower. The issues involved in deciding whether to use BFS include facility design, sterility
assurance, validation, and operational performance.
BFS offers some advantages over traditional aseptic processing. Automation and the use of a barrier system mean that fewer
personnel are needed in the fill room. Packaging in single-dose units requires no preservatives or antimicrobials. Glass containers
are replaced with safer, patient-friendly alternatives. All this streamlining decreases costs. Most issues in BFS are the
same as those confronting classic pharmaceuticals, but for biopharmaceuticals, additional concerns include the heat imparted
to the product during plastic extrusion, extractables from the plastic resin, and product stability.
The process. BFS containers are formed, filled, and sealed in one continuous, integrated operation within a single automated machine or
system. The process begins when low-density polyethylene resin pellets are melted and sterilized in an extruder at high temperatures
and pressures. The resin is then formed into plastic tubes (parisons). Molds close on the parisons, using vacuum holes and
hot knives to form containers. Then the containers are chilled in the molds and moved to the filling system where a HEPA-filtered
air shower protects the product as it is put in the containers. The molten necks of the containers are then sealed by the
chilled molds. Finally, the molds open and release the filled containers, which are conveyed for deflashing, inspection, and
packaging, while the molds return to the parison area.